Advances in the biological characterization of tumors has led to the design and development of anticancer agents targeting specific molecular alterations. The majority of these agents are designed to silence phosphorylation signals that are required for the development and maintenance of the cancer phenotype in specific tumor types. Prospective identification of cancer subsets containing particular target alterations is a requirement for these development programs, which in theory, should include smaller trials and result in larger therapeutic benefits. In this review, we will examine relevant examples of selection markers effectively utilized in oncology, and discuss important considerations pertaining to the co-development of drugs and diagnostics, including current regulatory paths, the incorporation of selection markers emerging late in development, and future directions in the area of personalized oncology.